The AIDS-defining illness Kaposi's sarcoma (KS) and several lines of evidences suggest that Kaposi's sarcoma-associated herpesvirus (KSHV) or HHV-8 is vital for KS pathogenesis. The long-term objective of this research is to examine the role of HHV-8 in the pathogenesis of KS. Serological studies conducted in the last funding period suggest that HHV-8 lytic replication precedes AIDS-KS. To determine the role of lytic replication in KS pathogenesis, the focus of the present study is on HHV-8 binding and entry interactions with host cells, with a rationale that these interactions per se may have a role in the pathogenesis of KS. In vitro and in vivo, HHV-8 has a broad tropism. Our studies show that this broad cellular tropism may be in part due to HHV-8's interaction with the ubiquitous host cell surface heparin sulfate (HS)-like molecules. HHV-8 envelope glycoprotein gB interacts with HS and rabbit anti-gB antibodies neutralized HHV-8 infection. Sequence analyses show that among the HHV-8 glycoproteins, and among all the gB of human and animal herpesviruses sequenced to date, only HHV-8 gB possesses the "RGD" (Arg-Gly-Asp) amino acids in the extracellular domain. The "RGD" amino acids is the minimal peptide region of many proteins known to interact with host cell integrins critical for the regulation of gene expression, cellular growth and differentiation. We hypothesize that HHV-8 envelope glycoprotein gB interaction with host cell surface integrins may play a vital role in the biology of HHV-8 infection and in the pathogenesis of HHV-8 associated KS. To examine this hypothesis, four major specific aims have been formulated: (1) To determine whether HHV-8 recognize host cell surface integrin molecules (2) To determine the role of integrins in HHV-8 interactions with host cells (3) To determine the interactions between HHV-8 gB and the cell surface integrins. (4) To determine the morphological and molecular consequences of HHV-8 and HHV-8 gB interactions with cell surface integrins. These studies are significant since they will provide an insight into the biology of HHV-8 and it's role in the pathogenesis of KS.